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PubMed2004

Reinforcing effects of methylphenidate: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs such as D-amphetamine, caffeine, and cocaine are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of methylphenidate under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral methylphenidate (0, 10, 20, and 40 mg) were assessed in seven healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session) and the order of relaxation and performance sessions was constant within a dose condition. RESULTS: Methylphenidate significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Methylphenidate produced comparable stimulant-like subject ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment suggest that the reinforcing effects of methylphenidate, like D-amphetamine and cocaine, are influenced by behavioral demands following drug administration.

Administration, Oral↗
PubMed1997

Effects of methylphenidate on spatial working memory and planning in healthy young adults.

Previous studies of the effects of the psychomotor stimulant, methylphenidate, have concentrated on vigilance and reaction time tasks. In this study, the effects of methylphenidate on more complex aspects of cognition were studied using tasks from the CANTAB battery and related tests which have been shown to be sensitive to frontal lobe dysfunction. Twenty-eight young healthy men participated in a counterbalanced, double-blind, placebo-controlled study of the effects of methylphenidate. Cognitive assessment included tests of spatial working memory, planning, verbal fluency, attentional set-shifting and sustained attention. Methylphenidate had significant effects on performance of the tests of spatial working memory and planning but not on the attentional and fluency tests. When the drug was taken on the first test session, performance on the spatial tests was enhanced by the drug compared to placebo. However, when the drug was taken second, performance accuracy was impaired whereas response latencies were decreased. These results are consistent with a hypothesis that methylphenidate influences performance in two conflicting ways; enhancing executive aspects of spatial function on novel tasks but impairing previously established performance. This pattern of effects is discussed within the framework of dual, interacting arousal mechanisms.

Adult↗
PubMed2004

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [123I]FP-CIT and a dedicated small animal SPECT.

PURPOSE: The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [123I]FP-CIT. METHODS: [123I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [123I]FP-CIT scans with bone metabolism and perfusion scans obtained with 99mTc-DPD and 99mTc-tetrofosmin, respectively. As these tracers do not pass the blood-brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [123I]FP-CIT scans with images of brain perfusion obtained with 99mTc-HMPAO. RESULTS: Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V''3) of 0.24+/-0.26 (mean +/- SD) and 1.09+/-0.42, respectively (t test, two-tailed, p<0.0001). Cortical V''3 values amounted to 0.05+/-0.28 (methylphenidate) and 0.3+/-0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [123I]FP-CIT accumulation. CONCLUSION: The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [123I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and small animal imaging systems.

Animals↗
PubMed2000

Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment.

Involvement of the dopaminergic system has been suggested in patients suffering from attention deficit hyperactivity disorder (ADHD) since the symptoms can be successfully treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). This study reports the findings on the status of the DAT in adults with ADHD before and after commencement of treatment with methylphenidate, as measured using [99mTc]TRODAT-1. Seventeen patients (seven males, ten females, aged 21-64 years, mean 38 years) were examined before and after the initiation of methylphenidate treatment (3x5 mg/day). All subjects were injected with 800 MBq [99mTc]TRODAT-1 and imaged 3 h p.i. Single-photon emission tomography (SPET) scans were acquired using a triple-headed gamma camera. For semiquantitative evaluation of the DAT, transverse slices corrected for attenuation were used to calculate specific binding in the striatum, with the cerebellum used as background [(STR-BKG)/BKG]. Data were compared with an age-matched control group. It was found that untreated patients presented with a significantly increased specific binding of [99mTc]TRODAT-1 to the DAT as compared with normal controls [(STR-BKG)/BKG: 1.43+/-0.18 vs 1.22+/-0.06, P<0.001]. Under treatment with methylphenidate, specific binding decreased significantly in all patients [(STR-BKG)/BKG: 1.00+/-0.14, P<0.001]. Our findings suggest that the number of DAT binding sites is higher in drug-naive patients suffering from ADHD than in normal controls. The decrease in available DAT binding sites under treatment with methylphenidate correlates well with the improvement in clinical symptoms. The data of this study help to elucidate the complex dysregulation of the dopaminergic neurotransmitter system in patients suffering from ADHD and the effect of treatment with psychoactive drugs.

Adult↗
PubMed1991

Exogenous tyrosine potentiates the methylphenidate-induced increase in extracellular dopamine in the nucleus accumbens: a microdialysis study.

Previous work has shown that the synthesis and release of dopamine may, under certain conditions, be influenced by an increase in the availability of its amino acid precursor, tyrosine. To examine whether exogenous tyrosine could potentiate the methylphenidate-induced increase in extracellular dopamine, male rats were implanted with microdialysis probes aimed at the right nucleus accumbens. Samples were collected from awake animals beginning 22 h after surgery. A repeated measures design was used involving the continuous collection of 20-min samples for a 4-h period once a day for 3 consecutive days. On a given day, an animal was infused with methylphenidate, tyrosine, or methylphenidate plus tyrosine. Periods of infusion with the active compounds were preceded and followed by baseline conditions, and treatments were counterbalanced to control for possible order effects. Methylphenidate plus tyrosine significantly increased extracellular levels of dopamine in comparison to drug alone. This effect was long-lasting, persisting into the post-treatment sampling period and peaking 40 min after the peak induced by methylphenidate alone. Tyrosine alone induced a small but significant increase in extracellular dopamine in the absence of any treatment to accelerate the firing of dopamine cells. These findings may have implications for the treatment of attention deficit hyperactivity disorder.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Dose response characteristics of methylphenidate on different indices of rats' locomotor activity at the beginning of the dark cycle.

Using a computerized infrared activity analysis system, the dose-response relationship, timing, and duration for stimulation of motor activity after a single dose of methylphenidate was studied in Sprague-Dawley rats. After 5 days of acclimation and 2 days of monitored baseline activity, rats received a single subcutaneous injection of vehicle or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate 1 h into the dark cycle. Recording was then resumed for an additional 36 h. Five locomotor indices were analyzed. Each locomotor parameter monitored different aspects of motor activity. The doses of 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) locomotor activity. The time to maximal effect (20, 50, and 90 min) and duration of effect (70, 210, and 280 min) increased with dose respectively. Ten mg/kg had the maximum effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. Single injections of methylphenidate did not alter motor activity the next day. Pharmacological parameters and specific locomotor parameters describing the effects of methylphenidate at the beginning of the dark cycle can later be used in chronopharmacologic studies. They will also provide the basis for investigation of adaptive mechanisms during repeated or chronic administration of methylphenidate.

Analysis of Variance↗
PubMed1981

Effect of methylphenidate on young adult's vigilance and event-related potentials.

Two studies were conducted on the effects of methylphenidate (20 mg) on young adults' event-related potentials. Although this stimulant elevated heart rate in study 1 (n = 14), it failed to affect either performance or amplitude of the late positive component (LPC) obtained from two versions of the continuous performance test (CPT). Because performance on these tasks was nearly error-free, we conducted study 2 (n = 23) to test the hypothesis that methylphenidate enlarges LPC amplitude only in more challenging tests than those used in study 1. In study 2, although heart rate was again elevated by the 20 mg dose of methylphenidate, LPC amplitude and performance were again unaffected in the two tasks employed in study 1 or in an easy tone discrimination procedure. However, in a more difficult version of CPT (10% errors of omission), both accuracy and amplitude of the concurrently obtained LPC were increased by methylphenidate. Similarly, in a choice-reaction time test, the stimulant increased speed as well as CNV amplitude. Our interpretation of the results is based on the view that LPC reflects the number of attentional resources committed to a stimulus during the evaluation stage. Thus, increases in LPC amplitude by methylphenidate are obtained only in tasks in which the subject may profit from the recruitment of additional attentional resources.

Adult↗
PubMed1983

Effects of two doses of methylphenidate on cross-situational and borderline hyperactive children's evoked potentials.

This study involved 27 children displaying cross-situational hyperactivity and 14 youngsters with borderline hyperactivity. For all patients, evoked potentials were recorded after receiving 0 (placebo), 0.3 and 0.6 mg/kg methylphenidate. Under each pharmacologic condition, subjects were administered: a photic stimulation procedure; two versions of the Continuous Performance Test (CPT), which varied in difficulty level; and a discrimination ('oddball') test. Under photic stimulation, methylphenidate reduced the impact of increasing brightness levels on the rates of amplitude increment and latency decrease in the P208 component of the visual evoked response. These results are similar to those obtained by Buchsbaum and Wender (1973) for hyperactive patients with a positive clinical response to amphetamine. In CPT and the discrimination test, the two active dosages of methylphenidate brought about a comparable reduction of placebo levels of errors and reaction time. Analogously, in both versions of CPT, the two active dosages resulted in comparable increases in the amplitude of two components of the late positive complex (LPC; P510 and P740). P510 was identified as a classical P300. In the discrimination test, the effect of the stimulant on the response evoked by the visual non-target was to increase the amplitude of a component (P463) previously identified as P300. These pharmacologic results were nearly identical for borderline and cross-situational patients. In general, the results confirmed previous observations that methylphenidate improves hyperactive children's performance and increases the amplitude of their LPC. Further, these findings support previous observations that hyperactive patients' cognitive processing is optimized by a dosage of 0.3 mg/kg methylphenidate. Finally, the similarity between findings for cross-situational and borderline hyperactive patients is consistent with other evidence that stimulant effects are not limited to classically hyperactive children.

Attention Deficit Disorder with Hyperactivity↗
PubMed1980

A comparison of the effects of methylphenidate and amphetamine on the simultaneous release of radiolabelled dopamine and p- or m-tyramine from rat striatal slices.

The release of [14C]dopamine (DA) from slices of rat caudate nucleus was studied simultaneously with the release of either [3H]para-tyramine (pTA) or [3H]meta-tyramine (mTA). Amphetamine (10(-5) M) caused a large concurrent release of [14C]DA and [3H]pTA; similar results were obtained when [14C]DA and [3H]mTA release were studied. The release of all three amines by amphetamine was quantitatively similar. In contrast, methylphenidate caused a release of [3H]pTA similar to that seen with amphetamine, but only a very small simultaneous release of [14C]DA. [3H]mTA was also strongly released by methylphenidate concurrent with a minimal release of [14C]DA. The inclusion of reserpine in the incubation medium had no detectable effect on the release of any of the three amines by amphetamine. Methylphenidate-induced release of tritiated mTA and pTA was also unaffected by reserpine. However, the release of [14C]DA by methylphenidate was potentiated in the presence of reserpine. The uptake of radiolabelled pTA, mTA and DA was inhibited by both amphetamine and methylphenidate, although amphetamine was a stronger inhibitor of the uptake of all three amines. It is suggested that release of endogenous tyramines may be involved in mediating some actions of psychomotor stimulant drugs.

Amphetamine↗
PubMed1996

Place preference and microdialysis studies with two derivatives of methylphenidate.

Conditioned place preference studies with derivatives of dl-threo-methylphenidate (Ritalin) which bear a bromine atom or a methoxy group on the para position of the phenyl ring are reported. Both derivatives, as well as methylphenidate itself, induced a significant increase in place preference when administered i/p to rats at 10 mg/Kg, compared with saline conditioned controls. The change for p-bromomethylphenidate was slightly greater than that seen for methylphenidate or p-methoxymethylphenidate. Extracellular dopamine in the striatum, and locomotor activity, were also increased by i/p administration of p-methoxymethylphenidate (20 mg/Kg) to a similar extent to the increases seen with this dose of methylphenidate or p-bromomethylphenidate in an earlier study (Pan et al. Eur. J. Pharmacol. 264: 177-182, 1994). Administration of p-methoxymethylphenidate failed to abolish increases in extracellular dopamine and locomotor activity induced by subsequent administration of cocaine (20 mg/Kg). It is concluded that the methylphenidate derivatives share the general pharmacological properties of other psychostimulant drugs.

Animals↗
PubMed1983

Effects of methylphenidate on rat endurance performance and neuromuscular transmission in vitro.

The studies were designed to evaluate the effects of methylphenidate on endurance performance in vivo and on neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Methylphenidate produced a biphasic effect on treadmill endurance performance, increasing running times by 41-61% at 2.5-5 mg/kg, while reducing running times by 35% at 20 mg/kg. A biphasic effect on nerve-stimulated muscle concentrations was also observed, with twitch tension increased by up to 49-106% at low concentrations (0.1-0.3 mM) and blocked at high concentrations (0.6-1.0 mM). Tissues obtained from rats pretreated with alpha-methyl-p-tyrosine or reserpine exhibited no change in twitch height. Methylphenidate failed to protect against irreversible blocking of the twitch by alpha-bungarotoxin and did not modify the resting membrane potential, miniature endplate potential (MEPP) frequency or nerve-stimulated acetylcholine release. High concentrations reduced the amplitudes of the MEPP and endplate potential. Whereas methylphenidate and amphetamine both produced biphasic effects on skeletal muscle contractions in vitro, they act by different neuropharmacological mechanisms. Unlike amphetamine, the biphasic effects of methylphenidate are produced by mechanisms that are independent of cholinergic or adrenergic interactions and may involve direct effects on the muscle.

Acetylcholine↗
PubMed1994

Effects of methamphetamine and methylphenidate on single and paired rat open-field behaviors.

The present study used a video analysis system to investigate the effects of indirect dopamine agonists, methamphetamine and methylphenidate, on single and paired rat open-field behaviors. Experimental rats were injected with saline, methamphetamine, or methylphenidate (0.008, 0.04, 0.2, 1.0, 5.0 mg/kg, IP) and put into an open field for 30 min singly or paired with another rat. The rats' movements were plotted on XY coordinates by a video analysis system every 0.5 s and analyzed by distance and time factors. When paired, the experimental rats moved more than when single, and the total move distance increased according to dose of methamphetamine or methylphenidate. Further analysis showed that under methamphetamine, fleeing distances increased significantly but chasing distances were not affected; under methylphenidate, fleeing distances also increased, but chasing distances decreased significantly. Although two rats in an open field often stand in contact with each other, both methamphetamine and methylphenidate in doses exceeding 1.0 mg/kg tended to keep the two rats separate. These phenomena indicate that the two indirect dopamine agonists induce less interaction and decrease social behavior.

Animals↗
PubMed1989

Methylphenidate and pemoline do not cause depletion of rat brain monoamine markers similar to that observed with methamphetamine.

Methylphenidate (Ritalin) and pemoline (Cylert) are central nervous system stimulants which are widely prescribed for attention deficit and other psychiatric disorders. Several other related stimulants, including amphetamine and methamphetamine, have been shown to cause long lasting decreases in monoamine markers in rat brain, characteristic of axonal degeneration. To assess the neurotoxic potential of methylphenidate and pemoline, we compared the effects of multiple injections (sc, bid for up to 4 days) of methylphenidate (21 and 50 mg/kg) and pemoline (20 and 70 mg/kg) with methamphetamine (5 and 15 mg/kg) on rat brain norepinephrine, dopamine, and serotonin levels and transport sites. While decreases were observed in all brain monoamine markers measured in rats treated with methamphetamine, no changes were observed in animals treated with methylphenidate as compared to saline-treated controls. Pemoline failed to induce significant changes in the level of monoamine transport sites; however, a wide array of changes were observed in the levels of 5-hydroxyindoleacetic acid, dopamine, and norepinephrine in various brain areas after a 3-day treatment regimen with a high dose (70 mg/kg) of pemoline. The lack of changes in monoamine transport sites following the repeated administration of high doses of methylphenidate and pemoline suggests that these drugs do not affect axonal integrity. However, the pattern of changes observed in the levels of monoamines after pemoline treatment may have relevance to the self-injurious behavior seen in these animals.

Animals↗
PubMed1976

The role of locomotion in conditioning methylphenidate-induced locomotor activity.

This experiment determined whether overt performance of the entire response (actual running) was necessary for the conditioning of methylphenidate-induced locomotor activity (wheel-running) in guinea pigs. Four guinea pigs were given daily injections of 2.5 mg/kg methylphenidate and were allowed to run in activity wheels; 4 other guinea pigs were given methylphenidate and were placed in locked activity wheels; a third group of 4 guinea pigs were administered saline and allowed to locomote; a fourth group of 4 guinea pigs received saline injections and were placed in locked activity wheels. After 12 days of injection, all animals were given saline injections on the 9 subsequent days and allowed to run freely in the wheels. The 2 groups which had received methylphenidate showed more locomotor activity than the saline injected animals but were not distinguishable from each other on the basis of prior opportunity to engage in locomotor activity. These results were interpreted to indicate that (a) increased methylphenidate-induced locomotor activity may be conditioned with repeated administration of the drug, and (b) actual running is not essential for the conditioning of drug-induced wheel-running.

Adaptation, Psychological↗
PubMed1982

Intragastric methylphenidate does have effects on the behavior of rats.

The effects of intraperitoneal (2.0-32 mg/kg) and intragastric (8.0-96 mg/kg) methylphenidate on milk intake were determined in two groups of rats. Experimental sessions consisted of 15 min access to a sweetened milk solution each day, seven days a week. Following the determination of baseline intake, a dose of methylphenidate was administered prior to the session once every four days with all rats in each group receiving all doses. Although methylphenidate was equally effective in decreasing milk intake using either route of administration, intraperitoneal methylphenidate was four times as potent as intragastric methylphenidate.

Animals↗
PubMed1993

A comparison of the motor-activating effects of acute and chronic exposure to amphetamine and methylphenidate.

Acute exposure to methylphenidate (0.0, 5.0, 10.0, or 20.0 mg/kg) or amphetamine (0.0, 0.5, 1.0, 2.0, or 4.0 mg/kg) dose-dependently increased horizontal activity. The amphetamine-induced increase in activity was progressively augmented with repeated exposures over 7 days. In contrast, methylphenidate (20.0 mg/kg)-induced increases in activity became smaller with repeated exposures. Subthreshold doses of methylphenidate (1.0 or 5.0 mg/kg) were ineffective in stimulating motor activity even after 7 daily exposures. These findings suggest that, although sensitization develops with chronic amphetamine treatment, the consequence of chronic exposure to methylphenidate is tolerance. These data are discussed in terms of the different mechanisms through which methylphenidate and amphetamine affect central dopamine release.

Amphetamine↗
PubMed1990

Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone.

The acute pharmacological actions of methylphenidate, a potent psychotogenic stimulant, were studied by measuring plasma homovanillic acid (HVA) and serum growth hormone (GH) as indices of presynaptic and postsynaptic functions, respectively. Twenty psychiatric inpatients participated in a double-blind, placebo-randomized study of methylphenidate infusion. Multiple samples of plasma HVA and GH were measured before and up to 24 hours after both methylphenidate and placebo infusions. There was a robust and significant GH response during the 2-hour postmethylphenidate period when compared to placebo. The peak response was significantly greater in male patients than in female patients. Although there were no changes in plasma HVA during the 2 hours following the infusion, there was a significant decrease in HVA 24 hours after methylphenidate as compared to preinfusion baseline values. Plasma HVA values also tended to be lower 24 hours after methylphenidate when compared to the corresponding postplacebo value. Schizophrenic patients did not differ significantly from nonschizophrenic patients in their physiological or biochemical responses.

Adult↗
PubMed2005

Actions of methylphenidate on dopaminergic neurons of the ventral midbrain.

BACKGROUND: Methylphenidate has been suggested to exert its therapeutic effect mainly by blocking the dopamine transporter. In spite of the importance of this interaction, no detailed information is available yet on its actions on single dopaminergic neurons. METHODS: We examined the effects of methylphenidate on dopaminergic neurons using electrophysiological recordings from rat midbrain slices. RESULTS: Methylphenidate inhibited spontaneous firing and caused a membrane hyperpolarization in current clamp or an outward current in voltage clamp. These effects were antagonized by the D(2) receptor antagonist sulpiride. An acute dopamine-depleting treatment of the slices with the dopa-decarboxylase inhibitor carbidopa significantly reduced the effects of methylphenidate. This drug potentiated, in a concentration-dependent manner, cellular responses to exogenous dopamine application. CONCLUSIONS: Our electrophysiological data are consistent with the hypothesis that methylphenidate inhibits dopamine transporter and suggest that the depression of firing is mediated by the release of newly synthesized dopamine which accumulates extracellularly due to inhibition of its reuptake.

Action Potentials↗